oxolane-2-carbonyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stream of diazomethane (from N-methyl-N-nitrosotoluene-4-sulphonamide, 18.0g) in argon (P. Lombardi, Chem. and Ind., 1990, (21), 708) was passed into a solution of (RS)-tetrahydrofuroyl chloride [prepared from (RS)-tetrahydrofuroic acid (3.48g, 30mmol) as described in Example 2(a)] in dichloromethane (60ml) cooled in an ice bath. When the diazomethane addition was complete, 48% aqueous hydrogen bromide (5.6ml, 33.2mmol) was added. The mixture was stirred 0.25h then washed twice with water, dried, concentrated and flash chromaographed on silica gel eluting with 10% ethyl acetate in hexane to give the title compound as a pale yellow oil (4.44g, 77%); vmax (CH2Cl2) 1733, 1245, 1073 and 938cm-1 ; δH (CDCl3) 1.85-2.35 (4H, m), 3.85-4.05 (2H, m), 4.20 (2H, s), 4.54 (1H, dd, J 6.1, 8.2Hz). [Mass spectrum: +ve ion (ammonia) MNH4+ (210)]. cooled in an ice bath then washed twice with water dried concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Oxalyl chloride (5.2ml, 60mmol) and DMF (1 drop) were added to (RS)-2-tetrahydrofuroic acid (W. E. Kaufmann and R. Adams, J.Amer.Chem.Soc., 1923, 45, 3029) (4.64g, 40mmol) in dichloromethane (25ml). The mixture was stirred 1h, evaporated in vacuo, dichloromethane added and reevaporated to give 2-tetrahydrofuroyl chloride, vmax (CH2Cl2) 1795cm-1. 2-Tetrahydrofuroyl chloride in ether (25ml) and dichloromethane (10ml) was added dropwise to an ice bath cooled solution of diazomethane (ca 80mmol) in ether (150ml). The reaction mixture was stirred 0.25h then a stream of hydrogen chloride gas passed into the solution for ca 2 minutes then stirred a further 0.25h, washed with saturated brine, dried, concentrated and flash chromatographed on silica gel eluting with 5,7.5 and 10% ethyl acetate in hexane to provide the title compound (2.46g, 41%); (Found: M+, 148.0279. C6H ClO2 requires M, 148.0291); vmax (CH2Cl2) 1739, 1395, 1071 and 936cm-1 ; δH (CDCl3, 250MHz) 1.8-2.4 (4H, m) and 3.9-4.6 (5H, m). washed with saturated brine dried concentrated flash chromatographed on silica gel eluting with 5,7.5 and 10% ethyl acetate in hexane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (8.73 g, 10 mmol) in N,N-dimethylacetamide (30 mL), was added in drops tetrahydro-2-furancarbonyl chloride (1.8 g, 13 mmol) (prepared as in part A of Example 18) at 0°-5°. After the addition, the mixture was stirred at 0°-5° for 0.5 hour, then at room temperature for 20 hours. Nitrogen gas was purged through the solution for 0.25 hour, and the N,N-dimethylacetamide was removed in vacuo at 40°. The residue was dissolved in ethyl acetate (200 mL), and the solution was washed successively with cold aqueous sodium bicarbonate (2×50 mL), water (2×50 mL) and saturated sodium chloride (2×50 mL). After drying over sodium sulfate, the solvent was removed in vacuo to obtain the title B furanilide as an off-white foamy material (9.27 g, crude). The crude product (7.2 g), upon purification by column chromatography over silica gel (mobile phase: hexane/ethyl acetate) furnished N,N'-bis[2,3-bis (acetyloxy)propyl]-2,4,6-triiodo-5-[[(tetrahydro-2-furanyl)carbonyl]amino]-1,3-benzenedicarboxamide (6.19 g), m.p. 101°-104°. prepared as in part A of Example 18) at 0°-5° After the addition at room temperature for 20 hours Nitrogen gas was purged through the solution for 0.25 hour the N,N-dimethylacetamide was removed in vacuo at 40° The residue was dissolved in ethyl acetate (200 mL) the solution was washed successively with cold aqueous sodium bicarbonate (2×50 mL), water (2×50 mL) and saturated sodium chloride (2×50 mL) After drying over sodium sulfate the solvent was removed in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tetrahydrofuroyl chloride (15.0 g, 112 mmol) was added dropwise to a cold solution of benzyl alcohol (10.9 g, 101 mmol) and pyridine (20.0 g, 253 mmol) in Et2O (200 mL). The solution was stirred at 0° for 40 minutes, then filtered to remove the side product pyridine hydrochloride. The filtrate was washed with 0.1M HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL), and then dried over MgSO4. Filtration and evaporation of the solvent gave a yellow oil, which was distilled. Benzyl tetrahydrofuroate was obtained as a colorless oil (21.1 g), b.p. 118° to 120° at 0.5 mm Hg. filtered to remove the side product pyridine hydrochloride The filtrate was washed with 0.1M HCl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL) dried over MgSO4 Filtration and evaporation of the solvent gave a yellow oil, which was distilled

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-amino-5-bromothiophene-2-carboxamide (120 mg) produced in Example 1, step D, triethylamine (0.083 mL) and tetrahydrofuran (3.0 mL) was added tetrahydrofuran-2-carbonylchloride (80 mg) with stirring at room temperature. The reaction mixture was stirred for 10 min, and the reaction system was concentrated under reduced pressure. 2M Aqueous sodium hydroxide solution (1.0 mL) was added to the residue, and the mixture was stirred with heating at 120° C. for 2 hr. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (160 mg) as a pale-yellow solid. The reaction mixture was stirred for 10 min the reaction system was concentrated under reduced pressure 2M Aqueous sodium hydroxide solution (1.0 mL) was added to the residue the mixture was stirred with heating at 120° C. for 2 hr The mixture was extracted with ethyl acetate washed with brine dried over anhydrous sodium sulfate Insoluble material was removed by filtration the filtrate was concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-amino-5-bromothiophene-2-carboxamide (120 mg) produced in Example 1, step D, triethylamine (0.083 mL) and tetrahydrofuran (3.0 mL) was added tetrahydrofuran-2-carbonylchloride (80 mg) with stirring at room temperature. The reaction mixture was stirred for 10 min, and the reaction system was concentrated under reduced pressure. 2M Aqueous sodium hydroxide solution (1.0 mL) was added to the residue, and the mixture was stirred with heating at 120° C. for 2 hr. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (160 mg) as a pale-yellow solid. The reaction mixture was stirred for 10 min the reaction system was concentrated under reduced pressure 2M Aqueous sodium hydroxide solution (1.0 mL) was added to the residue the mixture was stirred with heating at 120° C. for 2 hr The mixture was extracted with ethyl acetate washed with brine dried over anhydrous sodium sulfate Insoluble material was removed by filtration the filtrate was concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 21) and 32.5 mg (0.24 mmol) of tetrahydrofuran-2-carbonyl chloride are reacted together by general method F. 40.9 mg (68.1% of theory) of the title compound are obtained.